The anthracycline glycoside antibiotics are those in which a tetrahydronaphthacene chromophore is linked to a sugar, most commonly a basic sugar. As representative of such antibiotics may be mentioned the following:
______________________________________ doxorubicin reticulomycin B daunorubicin isoquinocycline A daunorubicinol galirubin pyrromycin mycetin rutilantin mycetin A cinerubin A violacin cinerubin B .alpha.-citromycin aklavin .gamma.-citromycin rhodomycin A 10-deoxyrhodomycin rhodomycin B .beta.-isorhodomycin .gamma.-rhodomycin 1 .gamma.-isorhodomycin .gamma.-rhodomycin 2 .epsilon.-isorhodomycin .gamma.-rhodomycin 3 minomycin .gamma.-rhodomycin 4 aquayamycin isorhodomycin A ayamycin reticulomycin A nogalomycin doxorubicinol ______________________________________
Of these, doxorubicin (U.S. Pat. No. 3,590,028), daunorubicin (G.B. Pat. No. 1,003,383), and their derivatives and other analogs have gained wide attention as oncolytic agents, i.e., agents useful in the treatment of leukemia and in other cancer chemotherapy. In the formulas shown below and in the accompanying drawing, the structure of doxorubicin appears from Formula I (FIG. 1 of the drawing) wherein R.sub.1 is --COCH.sub.2 OH and R is the particular daunosaminil moiety depicted in Formula II (FIG. 2 of the drawing). When, instead, R.sub.1 is --COCH.sub.3, the structure of daunorubicin results. ##STR1## Many analogs of these compounds have been prepared, principally by operations on the hydroxymethyl ketone moiety of doxorubicin, the methyl ketone moiety of daunorubicin, and on the daunosaminil amino group of both compounds. Representative analogs are described in, e.g., U.S. Pat. No. 3,686,136; K. Yamamoto et al., J. Med. Chem., 15, 872 (1973); German Pat. Nos. 2,327,211; 2,557,537; and 1,920,198; E. Bachman et al., Agents and Actions 5/4, 383 (1975); P. Chandra, Cancer Chemother. Rep. 6, 115 (1975); F. Arcamone et al., id. at 123; and G. Zbinden et al., Cancer Chemother. Rep. 4, 707 (1975), the disclosures of which are incorporated herein by reference. As one derivative of especial interest may be mentioned rubidazone, i.e., the compound of Formula I wherein R is as in Formula II and R.sub.1 is --CCH.sub.3 NNHCO--C.sub.6 H.sub.5. Others are doxorubicinol and daunorubicinol.
One problem that has persistently attended the use of these oncolytic anthracycline glycosides arises from their high general, hematological, digestive and cardiac toxicity, which has restricted their more extensive use at doses adequate for effective cancer chemotherapy. The cardiotoxicity of these drugs has proven especially troublesome. Thus, severe cardiotoxicity, oftentimes lethal, attends the use of doxorubicin at cumulative doses in excess of 500 mg. per square meter. The problem of toxicity associated with doxorubicin doubtless has inspired the many attempts to modify the compound along useful lines, but as recently as 1975 one group of investigators was forced to conclude that "the compound which combines the strong and broad-spectrum antitumor activity of adriamycin [doxorubicin] with very low cardiac toxicity has not yet been identified." G. Zbinden et al., Cancer Chemother. Rep. 59, 707.
In the course of examining the cardiotoxicity of doxorubicin, I discovered it to be a potent inhibitor of the Na and K dependent cardiac membrane transport ATPase, and hence an inhibitor of K transport. I also observed that this inhibition was counteracted by calcium, suggesting that doxorubicin forms a complex with calcium. The cumulative cardiotoxicity of doxorubicin would be explained if the calcium-doxorubicin complex formed in blood was inactive in the ATPase while the small proportion of free glycoside bound essentially irreversibly to the enzyme. I concluded that tight monomeric metallic saturated derivatives of the anthracycline glcosides, such as derivatives embodying metal cations whose affinity for the polydentate ligands of the glycoside was greater than that of calcium, would be non-cardiotoxic. At the same time, the resulting modification might be insufficient to affect the mechanism of the drug's oncolytic activity, which may involve intercalation in the DNA of tumor cells. Whatever the mechanism of action, and I do not wish to be bound by any particular theory of efficacy, I have now prepared metal derivatives of anthracycline glycosides which, while retaining the anti-tumor efficacy of the parent compounds against transplanted tumors in mice, appear essentially to eliminate their characteristic cardiotoxicity. The new compounds present other significant advantages as well, as is reported hereinafter.
Some workers have reported complexes of metals with anthracycline glycosides. For example, D. W. Yesair et al., in A.A.C.R. Abstr. 285 (1974), reported that adriamycin [doxorubicin] and daunomycin [daunorubicin] complex with Fe(II), Co(II), Cu(II) and other metal cations. These workers combined Cu(II) and both adriamycin ("A") and daunomycin ("D"), reporting mole ratios for the latter of Cu(II):D (1:1), and concluded that "cuprous ions protect somewhat against delayed anthracycline toxicity." Subsequently, other investigators who attempted to confirm this work found that a 1:2:Cu(II):D polymer complex results from the Yesair method (50% of the metal cation remaining uncomplexed) but that, in vivo, "complete dissociation of the complex occurs immediately." K. Mailer et al., Biochem. Pharm. 25, 2085 (1976). These investigators concluded that effects previously observed in vivo "cannot be due to the presence of the chelate form of these drugs."
The metal derivatives of the anthracycline glycosides prepared according to the present invention are in essentially monomeric form (i.e., one glycoside per molecule of derivative), and undue polymerization which may, for example, prevent intercalation in the DNA of tumor cells, is essentially avoided by novel methods which discourage the active presence of free metal. At the same time, the compositions of this invention preferably include plural metal cations per molecule of anthracycline glycoside.